Ischemic stroke is sudden neurologic deficits that result from focal cerebral ischemia associated with permanent brain infarction (eg, positive diffusion-weighted MRI). Common causes are (from most to least common) nonthrombotic occlusion of small, deep cortical arteries (lacunar infarction); cardiogenic embolism; arterial thrombosis that decreases cerebral blood flow; and artery-to-artery embolism. Diagnosis is clinical, but CT or MRI is done to exclude hemorrhage and confirm the presence and extent of stroke. Thrombolytic therapy may be useful acutely in certain patients. Depending on the cause of stroke, carotid endarterectomy, antiplatelet drugs, or warfarin may help reduce risk of subsequent strokes.
Ischemia usually results from thrombi or emboli. Even infarcts classified as lacunar based on clinical criteria (morphology, size, and location) often involve small thrombi or emboli.
Atheromas, particularly if ulcerated, predispose to thrombi. Atheromas can occur in any major cerebral artery and are common at areas of turbulent flow, particularly at the carotid bifurcation. Partial or complete thrombotic occlusion occurs most often at the main trunk of the middle cerebral artery and its branches but is also common in the large arteries at the base of the brain, in deep perforating arteries, and in small cortical branches. The basilar artery and the segment of the internal carotid artery between the cavernous sinus and supraclinoid process are often occluded.
Less common causes of thrombosis include vascular inflammation secondary to disorders such as acute or chronic meningitis, vasculitic disorders, and syphilis; dissection of intracranial arteries or the aorta; hypercoagulability disorders (eg, antiphospholipid syndrome, hyperhomocysteinemia); hyperviscosity disorders (eg, polycythemia, thrombocytosis, hemoglobinopathies, plasma cell disorders); and rare disorders (eg, moyamoya disease, Binswanger's disease). Older oral contraceptive formulations increase risk of thrombosis.
Emboli may lodge anywhere in the cerebral arterial tree. Emboli may originate as cardiac thrombi, especially in the following conditions:
Other sources include clots that form after open-heart surgery and atheromas in neck arteries or in the aortic arch. Rarely, emboli consist of fat (from fractured long bones), air (in decompression sickness), or venous clots that pass from the right to the left side of the heart through a patent foramen ovale with shunt (paradoxical emboli). Emboli may dislodge spontaneously or after invasive cardiovascular procedures (eg, catheterization). Rarely, thrombosis of the subclavian artery results in embolic stroke in the vertebral artery or its branches.
Ischemic stroke can also result from lacunar infarcts. These small (≤ 1.5 cm) infarcts result from nonatherothrombotic obstruction of small, perforating arteries that supply deep cortical structures; the usual cause is lipohyalinosis (degeneration of the media of small arteries and replacement by lipids and collagen). Whether emboli cause lacunar infarcts is controversial. Lacunar infarcts tend to occur in elderly patients with diabetes or poorly controlled hypertension.
Less commonly, ischemic stroke results from vasospasm (eg, during migraine, after subarachnoid hemorrhage, after use of sympathomimetic drugs such as cocaine or amphetamines) or venous sinus thrombosis (eg, during intracranial infection, postoperatively, peripartum, secondary to a hypercoagulation disorder).
Inadequate blood flow in a single brain artery can often be compensated for by an efficient collateral system, particularly between the carotid and vertebral arteries via anastomoses at the circle of Willis and, to a lesser extent, between major arteries supplying the cerebral hemispheres. However, normal variations in the circle of Willis and in the caliber of various collateral vessels, atherosclerosis, and other acquired arterial lesions can interfere with collateral flow, increasing the chance that blockage of one artery will cause brain ischemia.
Some neurons die when perfusion is < 5% of normal for > 5 min; however, the extent of damage depends on the severity of ischemia. If it is mild, damage proceeds slowly; thus, even if perfusion is 40% of normal, 3 to 6 h may elapse before brain tissue is completely lost. However, if severe ischemia (ie, decrease in perfusion) persists > 15 to 30 min, all of the affected tissue dies (infarction). Damage occurs more rapidly during hyperthermia and more slowly during hypothermia. If tissues are ischemic but not yet irreversibly damaged, promptly restoring blood flow may reduce or reverse injury. For example, intervention may be able to salvage the moderately ischemic areas (penumbras) that often surround areas of severe ischemia (these areas exist because of collateral flow).
Mechanisms of ischemic injury include edema, microvascular thrombosis, programmed cell death (apoptosis), and infarction with cell necrosis. Inflammatory mediators (eg, IL-1B, tumor necrosis factor-α) contribute to edema and microvascular thrombosis. Edema, if severe or extensive, can increase intracranial pressure. Many factors may contribute to necrotic cell death; they include loss of ATP stores, loss of ionic homeostasis (including intracellular Ca accumulation), lipid peroxidative damage to cell membranes by free radicals (an iron-mediated process), excitatory neurotoxins (eg, glutamate), and intracellular acidosis due to accumulation of lactate.
Symptoms and Signs
Symptoms and signs depend on the part of brain affected. Patterns of neurologic deficits often suggest the affected artery (see Table 1: Stroke (CVA): Selected Stroke Syndromes), but correlation is often inexact.
Deficits may become maximal within several minutes of onset, typically in embolic stroke. Less often, deficits evolve slowly, usually over 24 to 48 h (called evolving stroke or stroke in evolution), typically in thrombotic stroke. In most evolving strokes, unilateral neurologic dysfunction (often beginning in one arm, then spreading ipsilaterally) extends without causing headache, pain, or fever. Progression is usually stepwise, interrupted by periods of stability. A stroke is considered submaximal when, after it is complete, there is residual function in the affected area, suggesting viable tissue at risk of damage.
Embolic strokes often occur during the day; headache may precede neurologic deficits. Thrombi tend to occur during the night and thus are first noticed on awakening. Lacunar infarcts may produce one of the classic lacunar syndromes (eg, pure motor hemiparesis, pure sensory hemianesthesia, ataxic hemiparesis, dysarthria–clumsy hand syndrome); signs of cortical dysfunction (eg, aphasia) are absent. Multiple lacunar infarcts may result in multi-infarct dementia.
Deterioration during the first 48 to 72 h after onset of symptoms, particularly progressively impaired consciousness, results more often from cerebral edema than from extension of the infarct. Unless the infarct is large or extensive, function commonly improves within the first few days; further improvement occurs gradually for up to 1 yr.
Diagnosis is suggested by sudden neurologic deficits referable to a specific arterial territory. Ischemic stroke must be distinguished from other causes of similar focal deficits (eg, hypoglycemia; postictal [Todd's] paralysis; hemorrhagic stroke; rarely, migraine). Headache, coma or stupor, and vomiting are more likely with hemorrhagic stroke.
Although diagnosis is clinical, neuroimaging and bedside glucose testing are mandatory. CT is done first to exclude intracerebral hemorrhage, subdural or epidural hematoma, and a rapidly growing, bleeding, or suddenly symptomatic tumor. CT evidence of even large anterior circulation ischemic stroke may be subtle during the first few hours; changes may include effacement of sulci or the insular cortical ribbon, loss of the gray-white junction between cortex and white matter, and a dense middle cerebral artery sign. After 24 h of ischemia, medium-sized to large infarcts are usually visible as hypodensities; small infarcts (eg, lacunar infarcts) may be visible only with MRI. Diffusion-weighted MRI (highly sensitive for early ischemia) can be done immediately after CT initial neuroimaging.
Distinction between lacunar, embolic, and thrombotic stroke based on history, examination, and neuroimaging is not always reliable, so tests to identify common or treatable causes and risk factors for all of these types of strokes are routinely done. These tests typically include carotid duplex ultrasonography, ECG, transesophageal echocardiography, and various blood tests (CBC, platelet count, PT/PTT, fasting blood glucose, lipid profile, homocysteine, ESR, and, for at-risk patients, syphilis serology). Troponin I level is measured to detect concomitant MI. Magnetic resonance or CT angiography is also often done. Other tests (eg, antiphospholipid antibodies) are done if certain disorders are suspected clinically.
Stroke severity and progression are often assessed using standardized measures such as the National Institutes of Health Stroke Scale (see Table 3: Stroke (CVA): The National Institutes of Health Stroke Scale*); the score on this scale correlates with extent of functional impairment and prognosis. During the first days, progression and outcome can be difficult to predict. Older age, impaired consciousness, aphasia, and brain stem signs suggest a poor prognosis. Early improvement and younger age suggest a favorable prognosis.
About 50% of patients with moderate or severe hemiplegia and most with milder deficits have a clear sensorium and eventually can take care of their basic needs and walk adequately. Complete neurologic recovery occurs in about 10%. Use of the affected limb is usually limited, and most deficits that remain after 12 mo are permanent. Subsequent strokes often occur, and each tends to worsen neurologic function. About 20% of patients die in the hospital; mortality rate increases with age.
Guidelines for early management of stroke are available from the Stroke Council of the American Heart Association/American Stroke Association. Patients with acute ischemic strokes are usually hospitalized. Supportive measures (see Stroke (CVA): Treatment) may be needed during initial evaluation and stabilization.
Perfusion of an ischemic brain area may require a high BP because autoregulation is lost; thus, BP should not be decreased except in the following situations:
If indicated, nicardipine 2.5 mg/h IV is given initially; dose is increased by 2.5 mg/h q 5 min to a maximum of 15 mg/h as needed to decrease systolic BP by 10 to 15%. Alternatively, IV labetalol can be used.
Patients with presumed thrombi or emboli may be treated with tPA, thrombolysis-in-situ, antiplatelet drugs, and/or anticoagulants. Most patients are not candidates for thrombolytic therapy; they should be given an antiplatelet drug (usually aspirin 325 mg po) when they are admitted to the hospital. Contraindications to antiplatelet drugs include aspirin- or NSAID-induced asthma or urticaria, other hypersensitivity to aspirin or to tartrazine, acute GI bleeding, G6PD deficiency, and use of warfarin.
Recombinant tPA is used for patients with acute ischemic stroke of < 3 h duration and no contraindications to tPA (see Table 4: Stroke (CVA): Exclusion Criteria for Use of Tissue Plasminogen Activator in Stroke*). Although tPA can cause fatal or other symptomatic brain hemorrhage, patients treated with tPA strictly following protocol have a higher likelihood of functional neurologic recovery. Thus, only physicians experienced in stroke management should use tPA to treat patients with acute stroke; inexperienced physicians are more likely to violate protocols, resulting in more brain hemorrhages and deaths. tPA must be given within 3 h of symptom onset—a difficult requirement. Because the precise time of symptom onset may not be known, clinicians must start timing from the moment the patient was last observed to be well. Before treatment with tPA, brain hemorrhage must be excluded by CT, and systolic BP must be < 185 mm Hg and diastolic BP < 110 mm Hg; antihypertensive drugs may be given as above. Dose of tPA is 0.9 mg/kg IV (maximum dose 90 mg); 10% is given by rapid IV injection, and the remainder by constant infusion over 60 min. Vital signs are closely monitored for 24 h after treatment, and BP is maintained below the target levels listed above. Any bleeding complications are aggressively managed. Anticoagulants and antiplatelet drugs are not used within 24 h of treatment with tPA.
Thrombolysis-in-situ (angiographically directed intra-arterial thrombolysis) of a thrombus or embolus can sometimes be used for major strokes if symptoms have begun > 3 h but < 6 h ago, particularly for strokes due to large occlusions in the middle cerebral artery. Clots in the basilar artery may be intra-arterially lysed up to 12 h after stroke onset, sometimes even later depending on the clinical circumstances. This treatment, although standard of care in some large stroke centers, is often unavailable in other hospitals.
Anticoagulation with heparin or low molecular weight heparin is used for stroke caused by cerebral venous thrombosis and is sometimes used for emboli due to atrial fibrillation and when stroke due to presumed progressive thrombosis continues to evolve despite use of antiplatelet drugs and cannot be treated any other way (eg, with tPA or invasive methods). Warfarin is begun simultaneously with heparin. Before anticoagulation, hemorrhage must be excluded by CT. Constant weight-based heparin infusion (see Fig. 2: Pulmonary Embolism: Weight-based heparin dosing.) is used to increase PTT to 1.5 to 2 times baseline values until warfarin has increased the INR to 2 to 3 (3 in hypercoagulable disorders). Because warfarin predisposes to bleeding and is continued after hospital discharge, its use should be restricted to patients likely to comply with dosage and monitoring requirements and not prone to falls.
Supportive care is continued during convalescence. Controlling general medical risk factors (especially hyperglycemia and fever) can limit brain damage after stroke, leading to better functional outcomes.
Carotid endarterectomy is indicated for patients with recent nondisabling, submaximal stroke attributed to an ipsilateral carotid obstruction of 70 to 99% of the arterial lumen or to an ulcerated plaque if life expectancy is at least 5 yr. In other symptomatic patients (eg, patients with TIAs), endarterectomy with antiplatelet therapy is indicated for carotid obstruction of ≥ 60% with or without ulceration if life expectancy is at least 5 yr. The procedure should be done by surgeons who have a morbidity and mortality rate of < 3% with the procedure in the hospital where it will be done. If carotid stenosis is asymptomatic, endarterectomy is beneficial only when done by very experienced surgeons, and that benefit is likely to be small. For many patients, carotid stenting with an emboli-protection device (a type of filter) is as effective as surgery.
Oral antiplatelet drugs are used to prevent subsequent strokes (secondary prevention). Aspirin 81 or 325 mg once/day, clopidogrel 75 mg once/day, or the combination product aspirin 25 mg/extended-release dipyridamole 200 mg bid may be used. In patients taking warfarin, antiplatelet drugs additively increase risk of bleeding and are thus usually avoided; however, aspirin is occasionally used simultaneously with warfarin in certain high-risk patients. The combination of clopidogrel and aspirin is avoided because it has no advantage over aspirin alone in secondary stroke prevention and results in more bleeding complications.
Transient Ischemic Attack
A transient ischemic attack (TIA) is focal brain ischemia that causes sudden neurologic deficits and is not associated with permanent brain infarction (eg, negative results on diffusion-weighted MRI). Diagnosis is clinical. Carotid endarterectomy, antiplatelet drugs, and warfarin decrease risk of stroke after certain types of TIA.
TIA is similar to ischemic stroke except that symptoms last < 1 h; most TIAs last < 5 min. Infarction is very unlikely if deficits resolve within 1 h. Deficits that resolve spontaneously within 1 to 24 h have been shown on diffusion-weighted MRI and other studies to often be accompanied by infarction and are thus no longer considered TIAs. TIAs are most common among the middle-aged and elderly. TIAs markedly increase risk of stroke, beginning in the first 24 h.
Most TIAs are caused by emboli, usually from carotid or vertebral arteries, although most of the causes of ischemic stroke (see Stroke (CVA): Etiology) can also result in TIAs. Uncommonly, TIAs result from impaired perfusion due to severe hypoxemia, reduced O2-carrying capacity of blood (eg, profound anemia, carbon monoxide poisoning), or increased blood viscosity (eg, severe polycythemia), particularly in brain arteries with preexisting stenosis. Systemic hypotension does not usually cause cerebral ischemia unless it is severe or arterial stenosis preexists because autoregulation maintains brain blood flow at near‑normal levels over a wide range of systemic BPs.
In subclavian steal syndrome, a subclavian artery stenosed proximal to the origin of the vertebral artery “steals” blood from the vertebral artery (in which blood flow reverses) to supply the arm during exertion, causing signs of vertebrobasilar ischemia.
Occasionally, TIAs occur in children with a severe cardiovascular disorder that produces emboli or a very high Hct.
Symptoms and Signs
Neurologic deficits are similar to those of strokes (see Table 1: Stroke (CVA): Selected Stroke Syndromes). Transient monocular blindness (amaurosis fugax), which usually lasts < 5 min, may occur when the ophthalmic artery is affected. Symptoms begin suddenly, usually last 2 to 30 min, then resolve completely. Patients may have several TIAs daily or only 2 or 3 over several years. Symptoms are usually similar in successive carotid attacks but vary somewhat in successive vertebrobasilar attacks.
Diagnosis is made retrospectively when sudden neurologic deficits referable to ischemia in an arterial territory resolve within 1 h. Isolated peripheral facial nerve palsy, loss of consciousness, or impaired consciousness does not suggest TIA. TIAs must be distinguished from other causes of similar symptoms (eg, hypoglycemia, migraine aura, postictal [Todd's] paralysis). Because an infarct, a small hemorrhage, and even a mass lesion cannot be excluded clinically, neuroimaging is required. Usually, CT is the study most likely to be immediately available. However, CT may not identify infarcts for > 24 h. MRI usually detects evolving infarction within hours. Diffusion-weighted MRI is the most accurate imaging test to rule out an infarct in patients with presumed TIA but is not always available.
The cause of a TIA is sought as for that of ischemic strokes, including tests for carotid stenosis, cardiac sources of emboli, atrial fibrillation, and hematologic abnormalities and screening for stroke risk factors. Because risk of subsequent ischemic stroke is high and immediate, evaluation proceeds rapidly, usually on an inpatient basis. It is not clear which patients, if any, can be safely discharged from the emergency department.
Treatment is aimed at preventing strokes; antiplatelet drugs are used (see Stroke (CVA): Acute). Carotid endarterectomy or arterial angioplasty plus stenting can be useful for some patients, particularly those who have no neurologic deficits but who are at high risk of stroke. Warfarin is indicated if cardiac sources of emboli are present. Modifying stroke risk factors, when possible, may prevent stroke.
Last full review/revision January 2007 by Elias A. Giraldo, MD, MS
Content last modified March 2012